October 15, 2009 (Vol. 29, No. 18)
Keith A. Markey Ph.D.
CSCs Are Believed Responsible for Tumorigenesis, Metastases, and Recurrence of Disease
The pharmaceutical and biotech industries have begun to develop targeted inhibitors of pathways that contribute to tumorigenesis and metastasis. These new medicines offer the promise of treating many types of cancer with greater efficacy and fewer unwanted side effects than heretofore possible. An important premise guiding this work is the cancer stem cell (CSC) hypothesis.
While normal stem cells are essential for development, play a key role in tissue maintenance, and aid in repair, cancer stem cells are believed responsible for tumorigenesis, metastases, and cancer recurrence. The first report providing evidence of CSCs identified primitive leukemic cells that could give rise to acute myeloid leukemia in immunodeficient mice.
Since that discovery in 1994, these cells have been found in most solid tumors. Skeptics of the CSC hypothesis have argued that cancer cells may be capable of de-differentiating and that isolation methods for CSCs do not select for all cells with the capacity for self-renewal. Regardless, the hypothesis provides an explanation for differences between cells in a tumor and offers a new rationale for drug design.
Moving from concept to clinic in just over a decade, CSC research has uncovered several promising pathways that a growing number of biopharmaceutical companies are exploring in clinical and preclinical studies.
The Notch pathway is an evolutionarily conserved system that regulates cell fate during development and in the adult. Its involvement in cancer depends upon its role in normal cells of that same tissue. If Notch acts as a gatekeeper of stem cells or regulator of precursor cell fate under normal conditions, it acts as an oncogene in promoting malignant growth. On the other hand, it is a tumor suppressor in tissues in which it normally initiates terminal differentiation.
Different points in the pathway have been targeted for drug development. OncoMed Pharmaceuticals’ OMP-21M18 is an antibody that blocks signals by binding to Delta-like ligand. The drug, which is in a clinical trial involving patients with advanced solid tumors, is part of a $1.4 billion collaboration with GlaxoSmithKline.
Merck and Roche have inhibitors to γ-secretase that cleaves the Notch receptor releasing the Notch intracellular domain, a transcription factor. Both companies’ drugs are in early testing against solid tumors. Finally, Trojantec is targeting the Notch pathway with a truncated version of Mastermind, a coactivator involved in chromatin-specific transcription. The drug may prove useful against tumors that overexpress Notch signaling components.
The PI3K/Akt pathway’s importance in cancer is partly attributable to PI3K’s (phosphatidylinositol 3-kinase’s) association with oncogenic growth factor receptors, notably for epidermal growth factor, platelet-derived growth factor, and mesenchymal transition factor. The pathway is also prone to mutations associated with oncogenesis, including changes in the catalytic subunit of PI3K that occur in prostate, breast, endometrium, urinary tract, and colon cancers.
Similarly, mutations of the lipid phosphatase PTEN that normally serves to deactivate the PI3K/Akt pathway are found in cancers of the endometrium, brain, skin, and prostate, while mutations in the protein kinase Akt, which is downstream of PI3K, are overexpressed in head and neck squamous cell carcinoma, and in pancreatic and ovarian cancers. Eight drugs targeting the PI3K/Akt pathway are in clinical trials.
Immunotherapies are under development against molecules on CSC surfaces that differ in quantity and/or quality from those on normal cells. ImmunoCellular Therapeutics’ ICT-121 vaccine elicits an immune response using a nine amino-acid epitope of the cell marker CD133.
The company is also developing mAbs that identify CSCs for destruction by the immune system. ICT-69, which was recently outlicensed to Roche, uses an antigen specific to ovarian cancer and multiple myeloma, while another project focuses on two cell adhesion molecules, CEACAM5 and -6, that are expressed by precancerous colon and breast cells.
MabCure has a similar program, but one that targets less-antigenic cell markers, based on an assumption that they have escaped immune detection. The company has prepared antibodies against ovarian, colorectal, and prostate cancers, as well as melanoma, for diagnostic tests, and later for therapeutic agents.
Molecular chaperones, or heat shock proteins (Hsps), are integral to protein production, protection from environmental stress, and identification of proteins for degradation. One, Hsp90, has been implicated in oncogenesis, as it is overexpressed in many tumors and may protect them from chemotherapy and radiation.
They may have use as monotherapies, though they probably will be used in combination with chemotherapy and radiotherapy, since blocking Hsp90 should render malignant cells more sensitive to these treatments. Trojantec has developed a derivative of the p21 gene to counter the effects of Hsp90.
The Hedgehog pathway provides an intercellular regulatory mechanism that serves essential functions in the normal proliferation and differentiation of stem cells. Mutations in this pathway figure in basal cell carcinoma, medulloblastoma, and other malignancies. Three drugs that interfere with hedgehog signaling are in clinical trials—two, Infinity Pharmaceuticals’ IPI-926 and Genentech/Curis’ GDC-0449, are derivatives of cyclopamine, which has been studied extensively.
Keith A. Markey, Ph.D. ([email protected]), is scientific director at Griffin Securities. Web: www.griffinsecurities.com.